This application is in response to PAR-12-039. Esophageal adenocarcinoma (EA) is the most common form of esophageal cancer in the US and western countries and incidence has increased by 675% over the past 30 years. Five-year survival is very poor at less than 20%. Thus, it is very critical to conduct studies to understand the etiology and develop the prevention strategies. Most EA arises in Barrett's Esophagus (BE), a condition of intestinal metaplasia in which the normal lining of the esophagus is replaced by intestinal-type tissue. The etiology of BE and EA are poorly understood and very few modifiable risk factors have been identified. Very recently, we found dietary intakes of vitamins involved in one-carbon metabolism (folate and vitamin B6) were inversely associated with both BE and EA risk among both smokers and non-smokers in a population-based case-control study suggesting that one-carbon metabolism is an important risk factor in esophageal carcinogenesis and its effect may be early in the carcinogenesis process. An important component of one-carbon metabolism is the methionine cycle. Methionine metabolism is integrally involved in most physiologic methylation reactions including DNA and RNA methylation. Aberrant DNA methylation is a key characteristic of both BE and EA. Methionine and its metabolic derivatives regulate the activity of most methyl-transferases and the activity of several enzymes involved in folate metabolism. S-adenosyl-methionine (SAM), the direct metabolite of methionine, is the methyl donor for nearly all methylation reactions in the body. SAM is irreversibly converted to S-adenosyl-homocysteine (SAH). We recently found higher plasma SAM levels were associated with decreased neoplasia risk in two studies; higher SAM levels were associated decreased colorectal adenoma, a cancer precursor, and with decreased risk of both low-grade and aggressive prostate cancers, a result consistent with the adenoma findings. Thus, there are preliminary data that SAM and SAH may have an effect early in carcinogenesis. Combined with our preliminary data that dietary one- carbon metabolism factors have a role in BE and EA risk, we hypothesize that methionine metabolism, and specifically SAM and SAH have a role in EA carcinogenesis. We propose to test this hypothesis in a pilot study using plasma samples from a population-based study of BE and EA. Included in the analysis will be 200 BE cases, 200 EA cases, and 200 healthy controls. This will be the first study to evaluate this novel hypothesis.